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Anti-VEGF Treatment for Prevention of PDR/DME

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT02634333
Recruitment Status : Active, not recruiting
First Posted : December 18, 2015
Last Update Posted : August 24, 2018
Sponsor:
Collaborators:
Regeneron Pharmaceuticals
Juvenile Diabetes Research Foundation
National Eye Institute (NEI)
National Institutes of Health (NIH)
Information provided by (Responsible Party):
Jaeb Center for Health Research

Brief Summary:

Multiple studies have implicated vascular endothelial growth factor VEGF as a major causative factor in human eye diseases characterized by neovascularization including proliferative diabetic retinopathy (PDR) and vascular permeability including diabetic macular edema (DME). While there is strong evidence that PDR outcomes are markedly reduced in eyes that are treated with monthly anti-VEGF therapy (A Study of Ranibizumab Injection in Subjects With Clinically Significant Macular Edema (ME) With Center Involvement Secondary to Diabetes Mellitus: RIDE/RISE) and moderately reduced in eyes that received fairly frequent dosing during the 1st year of treatment (Diabetic Retinopathy Clinical Research Network protocol I), it is unknown whether or not an earlier but less frequent dosing regimen would result in similar, favorable anatomic outcomes, and whether favorable anatomic outcomes subsequently would result in favorable visual acuity outcomes.

If this study demonstrates that intravitreous aflibercept treatment is effective and safe for reducing the onset of PDR or center involved- DME (CI-DME) in eyes that are at high risk for these complications, a new strategy to prevent vision threatening complications of diabetes will be available for patients. The application of intravitreous aflibercept earlier in the course of disease (i.e., at the time when an eye has baseline severe non-proliferative diabetic retinopathy) could help to reduce future potential treatment burden in patients, at the same time resulting in similar or better long-term visual outcomes, if PDR and DME are prevented.

The primary objectives of this protocol are to 1) determine the efficacy and safety of intravitreous aflibercept injections versus sham injections (observation) for prevention of PDR or CI-DME in eyes at high risk for development of these complications and 2) compare long-term visual outcomes in eyes that receive anti-VEGF therapy early in the course of disease with those that are observed initially, and treated only if high-risk PDR or CI-DME with vision loss develops.

Secondary objectives include:

  • Comparing other visual acuity outcomes between treatment groups, such as proportion of eyes with at least 10 or at least 15 letter loss from baseline, or gain or loss of at least 5 letters at the consecutive study visit just before and at the 2- or 4-year visit
  • Comparing optical coherence tomography (OCT) outcomes, such as mean change in OCT central subfield thickness and volume from baseline
  • Comparing proportion of eyes with at least 2 and 3-step worsening or improvement of diabetic retinopathy severity level (scale for individual eyes) by central reading center from baseline
  • Comparing associated treatment and follow-up exam costs between treatment groups
  • Comparing safety outcomes between treatment groups

Condition or disease Intervention/treatment Phase
Diabetic Retinopathy Diabetic Macular Edema Procedure: Prompt Sham Drug: Prompt aflibercept Procedure: Deferred laser Drug: Deferred aflibercept Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 328 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: Intravitreous Anti-Vascular Endothelial Growth Factor Treatment for Prevention of Vision Threatening Diabetic Retinopathy in Eyes at High Risk
Study Start Date : January 2016
Estimated Primary Completion Date : January 2020
Estimated Study Completion Date : January 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Sham Comparator: Observation (Prompt Sham)
Sham injection in study eye at randomization and at visits at 1, 2, and 4 months and then every 4 months thereafter. Deferred aflibercept may be given if center-involved diabetic macular edema or proliferative diabetic retinopathy develops and deferred laser may subsequently be added to intravitreal aflibercept if certain criteria are met.
Procedure: Prompt Sham
A sham injection (syringe without a needle pressed against the injection site) is performed on the day of randomization and visits at 1, 2, and 4 months and then every 4 months thereafter.

Procedure: Deferred laser
Laser (either focal/grid laser for diabetic macular edema or panretinal photocoagulation for proliferative diabetic retinopathy) is added following initiation of anti-vascular endothelial growth factor injections for center-involved diabetic macular edema or proliferative diabetic retinopathy only if certain criteria are met
Other Names:
  • focal/grid photocoagulation
  • panretinal photocoagulation

Drug: Deferred aflibercept
Intravitreal injection of 2.0mg aflibercept performed once proliferative diabetic retinopathy or center-involved diabetic macular edema develops and then up to every 4 weeks using defined treatment criteria.
Other Names:
  • intravitreal anti-vascular endothelial growth factor
  • Eylea

Experimental: Prompt aflibercept
Aflibercept injection in study eye at randomization and at visits at 1, 2, and 4 months and then every 4 months thereafter. More frequent aflibercept may be given if center-involved diabetic macular edema or proliferative diabetic retinopathy develops and deferred laser may subsequently be added to intravitreal aflibercept if certain criteria are met.
Drug: Prompt aflibercept
Intravitreal injection of 2.0mg aflibercept is performed on the day of randomization and visits at 1, 2, and 4 months and then every 4 months thereafter.
Other Names:
  • intravitreal anti-vascular endothelial growth factor
  • Eylea

Procedure: Deferred laser
Laser (either focal/grid laser for diabetic macular edema or panretinal photocoagulation for proliferative diabetic retinopathy) is added following initiation of anti-vascular endothelial growth factor injections for center-involved diabetic macular edema or proliferative diabetic retinopathy only if certain criteria are met
Other Names:
  • focal/grid photocoagulation
  • panretinal photocoagulation

Drug: Deferred aflibercept
Intravitreal injection of 2.0mg aflibercept performed once proliferative diabetic retinopathy or center-involved diabetic macular edema develops and then up to every 4 weeks using defined treatment criteria.
Other Names:
  • intravitreal anti-vascular endothelial growth factor
  • Eylea




Primary Outcome Measures :
  1. Development of proliferative diabetic retinopathy or diabetic macular edema defined as the first occurrence of any of the following (composite time-to-event outcome): [ Time Frame: 2 years ]

    Development = first occurrence of any of the following (composite time-to-event outcome):

    • Neovascularization (NV) within the 7-modified ETDRS fields on fundus photography or fluorescein angiogram (FA) by reading center grading
    • NV of the iris (≥2 cumulative clock hours), definitive NV of the angle, or neovascular glaucoma on clinical exam
    • Other documented outcomes from PDR: traction retinal detachment, vitreous hemorrhage, or pre-retinal hemorrhage greater than ½ disc area
    • Procedures undertaken for the treatment of PDR: PRP, anti-VEGF, or vitrectomy
    • Center involved-DME with ≥10% increase in central subfield thickness from baseline and either ≥10-letter decrease in visual acuity (VA) from baseline at a single visit or a 5-to-9-letter decrease in VA from baseline at 2 consecutive visits at least 21 days apart, with vision loss from DME
    • Non-topical treatment for DME performed without meeting the above criteria, including focal/grid laser or intravitreous injections for DME



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age >= 18 years
  2. Diagnosis of diabetes mellitus (type 1 or type 2)

    • Any one of the following will be considered to be sufficient evidence that diabetes is present:

    1. Current regular use of insulin for the treatment of diabetes
    2. Current regular use of oral anti-hyperglycemia agents for the treatment of diabetes
    3. Documented diabetes by American Diabetes Association and/or World Health Organization criteria
  3. Able and willing to provide informed consent.

Meets all of the following ocular criteria in at least one eye:

  1. Best corrected Electronic-Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity letter score ≥79 (approximate Snellen equivalent 20/25 or better)
  2. Severe non-proliferative diabetic retinopathy (NPDR) (based on the 4:2:1 rule) evident on clinical examination and on digital imaging as judged by the investigator. Reading center grading of less than ETDRS level 43 or greater than 53 is an exclusion.

    Severe NPDR is defined as:

    1. All 4 midperipheral quadrants show severe hemorrhages or microaneurysms (at least as great as Standard photograph 2A, approximately 20 dot and blot hemorrhages), or
    2. At least 2 fields of definite venous beading in the midperipheral quadrants or at least 1 field at least as severe as Standard photograph 6A, or
    3. At least 1 field of moderate intraretinal microvascular abnormalities (IRMA) in the midperipheral quadrants, at least as severe as Standard photograph 8A
  3. No evidence of neovascularization on clinical exam including active neovascularization of the iris (small iris tufts are not an exclusion) or angle neovascularization (if the angle is assessed).
  4. No evidence of neovascularization (NV) on fluorescein angiography within the 7-modified ETDRS fields, confirmed by the central Reading Center prior to randomization.

    • The widest method of imaging available at the site must be used to document whether there is NV present in the periphery; however, presence of NV outside of the 7-modified ETDRS fields on ultrawide field imaging will not be an exclusion provided treatment is not planned.

  5. No center-involved diabetic macular edema (CI-DME) on clinical exam and optical coherence tomography (OCT) central subfield thickness must be below the following gender and OCT-machine specific thresholds:

    1. Zeiss Cirrus: 290 µm in women and 305 µm in men
    2. Heidelberg Spectralis: 305 µm in women and 320 µm in men
    3. Investigator and potential participant are comfortable withholding treatment for DME until there is at least a 10% increase in OCT central subfield thickness with confirmed visual acuity loss (10 letter loss at a single visit or 5 to 9 at two consecutive visits).
  6. Prompt panretinal photocoagulation (PRP) or anti-vascular endothelial growth factor (anti-VEGF) treatment not required AND investigator and potential participant are willing to wait for development of high-risk characteristics (defined in protocol) to treat PDR.
  7. Media clarity, pupillary dilation, and study participant cooperation sufficient to obtain adequate fundus photographs, fluorescein angiogram, and OCT.

    • Investigator must verify accuracy of OCT scan by ensuring it is centered and of adequate quality (including segmentation line placement)

Exclusion Criteria:

  1. History of chronic renal failure requiring dialysis or kidney transplant.
  2. A condition that, in the opinion of the investigator, would preclude participation in the study (e.g., unstable medical status including blood pressure, cardiovascular disease, and glycemic control).
  3. Initiation of intensive insulin treatment (a pump or multiple daily injections) within 4 months prior to randomization or plans to do so in the next 4 months.
  4. Participation in an investigational trial that involved treatment within 30 days of randomization with any drug that has not received regulatory approval for the indication being studied.

    • Note: study participants cannot participate in another investigational trial that involves treatment with an investigational drug while participating in the study.

  5. Known allergy to any component of the study drug or any drug used in the injection prep (including povidone iodine prep).
  6. Known allergy to fluorescein dye.
  7. Blood pressure > 180/110 (systolic above 180 or diastolic above 110). • If blood pressure is brought below 180/110 by anti-hypertensive treatment, individual can become eligible.
  8. Systemic anti-VEGF or pro-VEGF treatment within 4 months prior to randomization.

    • These drugs should not be used during the study.

  9. For women of child-bearing potential: pregnant or lactating or intending to become pregnant within the next 2 years.

    • Women who are potential study participants should be questioned about the potential for pregnancy. Investigator judgment is used to determine when a pregnancy test is needed.

  10. Individual is expecting to move out of the area of the clinical center to an area not covered by another Diabetic Retinopathy Clinical Research Network certified clinical center during the next 2 years.

Individual has any of the following ocular characteristics in the eye(s) being evaluated:

  1. Exam or photographic evidence of vitreous hemorrhage or preretinal hemorrhage presumed to be from PDR.
  2. History of prior vitreous hemorrhage or preretinal hemorrhage presumed to be from PDR.
  3. History of prior PRP (defined as ≥100 burns outside of the posterior pole).
  4. An ocular condition is present (other than diabetic retinopathy) that, in the opinion of the investigator, might alter visual acuity during the course of the study (e.g., retinal vein or artery occlusion, uveitis or other ocular inflammatory disease, vitreomacular traction, etc.).
  5. History of DME or diabetic retinopathy treatment with laser or intraocular injections of medication within the prior 12 months and no more than 4 prior intraocular injections at any time in the past.

    • Enrollment will be limited to a maximum of 25% of the planned sample size with any history of treatment for DME and/or diabetic retinopathy. Once this number of eyes has been enrolled, any history of treatment for DME and/or diabetic retinopathy will be an exclusion criterion.

  6. History of major ocular surgery (including cataract extraction, scleral buckle, any intraocular surgery, etc.) within prior 4 months or anticipated within the next 6 months following randomization.
  7. Any history of vitrectomy.
  8. History of yttrium aluminum garnet capsulotomy performed within 2 months prior to randomization.
  9. Aphakia.
  10. Exam evidence of severe external ocular infection, including conjunctivitis, chalazion, or substantial blepharitis.
  11. Evidence of uncontrolled glaucoma.

    • Intraocular pressure must be <30, with no more than one topical glaucoma medication, and no documented glaucomatous field loss for the eye to be eligible.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02634333


  Hide Study Locations
Locations
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United States, Arizona
Arizona Retina and Vitreous Consultants
Phoenix, Arizona, United States, 85021
University of Arizona Medical Center/Department of Ophthalmology
Tucson, Arizona, United States, 85711
United States, California
Atlantis Eye Care
Huntington Beach, California, United States, 92647
Loma Linda University Health Care, Department of Ophthalmology
Loma Linda, California, United States, 92354
East Bay Retina Consultants, Inc.
Oakland, California, United States, 94609
Southern California Desert Retina Consultants, MC
Palm Desert, California, United States, 92211
Shashi D Ganti, MD PC
Porterville, California, United States, 93257
Retina Consultants of Southern California
Redlands, California, United States, 92374
U.C. Davis Eye Center
Sacramento, California, United States, 95817
California Retina Consultants
Santa Barbara, California, United States, 93103
Retinal Consultants of Southern California Medical Group, Inc.
Westlake Village, California, United States, 91361
United States, Connecticut
New England Retina Associates
Hamden, Connecticut, United States, 06518
United States, Florida
Retina Group of Florida
Fort Lauderdale, Florida, United States, 33308
National Ophthalmic Research Institute
Fort Myers, Florida, United States, 33912
University of Florida College of Med., Department of Ophthalmology, Jacksonville Health Science Cent
Jacksonville, Florida, United States, 32209
Florida Retina Consultants
Lakeland, Florida, United States, 33805
Bascom Palmer Eye Institute
Miami, Florida, United States, 33136
Magruder Eye Institute
Orlando, Florida, United States, 32803
Florida Retina Institute
Orlando, Florida, United States, 32806
Southeast Eye Institute, P.A. dba Eye Associates of Pinellas
Pinellas Park, Florida, United States, 33782
Fort Lauderdale Eye Institute
Plantation, Florida, United States, 33324
Sarasota Retina Institute
Sarasota, Florida, United States, 34239
Retina Associates of Florida, P.A.
Tampa, Florida, United States, 33609
United States, Georgia
Emory Eye Center
Atlanta, Georgia, United States, 30322
Southeast Retina Center, P.C.
Augusta, Georgia, United States, 30909
Marietta Eye Clinic
Marietta, Georgia, United States, 30060
Thomas Eye Group
Sandy Springs, Georgia, United States, 30328
United States, Illinois
Gailey Eye Clinic
Bloomington, Illinois, United States, 61704
Northwestern Medical Faculty Foundation
Chicago, Illinois, United States, 60611
University of Illinois at Chicago Medical Center
Chicago, Illinois, United States, 60612
Springfield Clinic, LLP
Springfield, Illinois, United States, 62703
United States, Indiana
Raj K. Maturi, M.D., P.C.
Indianapolis, Indiana, United States, 46290
United States, Iowa
Medical Associates Clinic, P.C.
Dubuque, Iowa, United States, 52002
Wolfe Eye Clinic
West Des Moines, Iowa, United States, 50266
United States, Kansas
Retina Associates, P.A.
Shawnee Mission, Kansas, United States, 66204
United States, Kentucky
Paducah Retinal Center
Paducah, Kentucky, United States, 42001
United States, Louisiana
Eye Associates of Northeast Louisiana dba Haik Humble Eye Center
West Monroe, Louisiana, United States, 71291
United States, Maryland
Elman Retina Group, P.A.
Baltimore, Maryland, United States, 21237
Wilmer Eye Institute at Johns Hopkins
Baltimore, Maryland, United States, 21287
Mid Atlantic Retina Specialists
Hagerstown, Maryland, United States, 21740
United States, Massachusetts
Valley Eye Physicians and Surgeons
Ayer, Massachusetts, United States, 01432
Joslin Diabetes Center
Boston, Massachusetts, United States, 02215
United States, Michigan
Henry Ford Health System, Dept of Ophthalmology and Eye Care Services
Detroit, Michigan, United States, 48202
Vitreo-Retinal Associates
Grand Rapids, Michigan, United States, 49546
United States, Minnesota
Retina Center, PA
Minneapolis, Minnesota, United States, 55404
United States, Missouri
Mid-America Retina Consultants, P.A.
Kansas City, Missouri, United States, 64111
United States, New Jersey
Retinal and Ophthalmic Consultants, PC
Northfield, New Jersey, United States, 08225
United States, New Mexico
Eye Associates of New Mexico
Albuquerque, New Mexico, United States, 87109
United States, New York
The New York Eye and Ear Infirmary/Faculty Eye Practice
New York, New York, United States, 10003
MaculaCare
New York, New York, United States, 10021
University of Rochester
Rochester, New York, United States, 14642
Retina-Vitreous Surgeons of Central New York, PC
Syracuse, New York, United States, 13224
United States, North Carolina
Western Carolina Clinical Research, LLC
Asheville, North Carolina, United States, 28803
Kittner Eye Center
Chapel Hill, North Carolina, United States, 27517
Charlotte Eye, Ear, Nose and Throat Assoc., PA
Charlotte, North Carolina, United States, 28210
United States, Ohio
Retina Associates of Cleveland, Inc.
Beachwood, Ohio, United States, 44122
University Hospitals Cleveland Medical Center
Cleveland, Ohio, United States, 44106
United States, Oregon
Oregon Retina, LLP
Eugene, Oregon, United States, 97401
Retina Northwest, PC
Portland, Oregon, United States, 97210
Casey Eye Institute
Portland, Oregon, United States, 97239
United States, Pennsylvania
Retina Vitreous Consultants
Monroeville, Pennsylvania, United States, 15146
University of Pennsylvania Scheie Eye Institute
Philadelphia, Pennsylvania, United States, 19104
United States, South Carolina
Carolina Retina Center
Columbia, South Carolina, United States, 29223
Palmetto Retina Center
West Columbia, South Carolina, United States, 29169
United States, Tennessee
Southeastern Retina Associates
Chattanooga, Tennessee, United States, 37421
Southeastern Retina Associates, P.C.
Knoxville, Tennessee, United States, 37909
United States, Texas
Southwest Retina Specialists
Amarillo, Texas, United States, 79106
Austin Retina Associates
Austin, Texas, United States, 78705
Retina Research Center
Austin, Texas, United States, 78705
Robert E. Torti, MD, PA dba Retina Specialists
DeSoto, Texas, United States, 75115
Retina Center of Texas
Grapevine, Texas, United States, 76051
Retina and Vitreous of Texas
Houston, Texas, United States, 77025
Baylor Eye Physicians and Surgeons
Houston, Texas, United States, 77030
Retina Consultants of Houston, PA
Houston, Texas, United States, 77030
Texas Retina Associates
Lubbock, Texas, United States, 79424
Valley Retina Institute
McAllen, Texas, United States, 78503
Retinal Consultants of San Antonio
San Antonio, Texas, United States, 78240
United States, Virginia
Retina Institute of Virginia
Richmond, Virginia, United States, 23235
Virginia Commonwealth University, Dept. of Ophthalmology
Richmond, Virginia, United States, 23298
United States, Wisconsin
University of Wisconsin-Madison, Dept of Ophthalmology/Retina Service
Madison, Wisconsin, United States, 53705
Canada, British Columbia
UBC/VCHA Eye Care Centre
Vancouver, British Columbia, Canada, V5Z 3N9
Canada, Nova Scotia
Nova Scotia District Health Authority
Halifax, Nova Scotia, Canada, B3H 2Y9
Canada, Ontario
Toronto Retina Institute (TRI)
North York, Ontario, Canada, M3C 0G9
University Health Network - Toronto Western Hospital
Toronto, Ontario, Canada, M5T 2S8
Sponsors and Collaborators
Jaeb Center for Health Research
Regeneron Pharmaceuticals
Juvenile Diabetes Research Foundation
National Eye Institute (NEI)
National Institutes of Health (NIH)
Investigators
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Study Chair: Jennifer K. Sun, MD, MPH Joslin Diabetes Center

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Responsible Party: Jaeb Center for Health Research
ClinicalTrials.gov Identifier: NCT02634333     History of Changes
Other Study ID Numbers: DRCR.net Protocol W
EY14231 ( Other Grant/Funding Number: National Eye Institute )
EY23207 ( Other Grant/Funding Number: National Eye Institute )
EY18817 ( Other Grant/Funding Number: National Eye Institute )
First Posted: December 18, 2015    Key Record Dates
Last Update Posted: August 24, 2018
Last Verified: August 2018

Keywords provided by Jaeb Center for Health Research:
anti-vascular endothelial growth factor
nonproliferative diabetic retinopathy

Additional relevant MeSH terms:
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Macular Edema
Retinal Diseases
Diabetic Retinopathy
Macular Degeneration
Retinal Degeneration
Eye Diseases
Diabetic Angiopathies
Vascular Diseases
Cardiovascular Diseases
Diabetes Complications
Diabetes Mellitus
Endocrine System Diseases
Mitogens
Endothelial Growth Factors
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Growth Substances
Physiological Effects of Drugs